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REVIEWS
Chronic migraine—classification,
characteristics and treatment
Hans-Christoph Diener, David W. Dodick, Peter J. Goadsby, Richard B. Lipton, Jes Olesen
and Stephen D. Silberstein
Abstract | According to the revised 2nd Edition of the International Classification of Headache Disorders,
primary headaches can be categorized as chronic or episodic; chronic migraine is defined as headaches in
the absence of medication overuse, occurring on ≥15 days per month for ≥3 months, of which headaches on
≥8 days must fulfill the criteria for migraine without aura. Prevalence and incidence data for chronic migraine
are still uncertain, owing to the heterogeneous definitions used to identify the condition in population-based
studies over the past two decades. Chronic migraine is severely disabling and difficult to manage, as affected
patients experience substantially more-frequent headaches, comorbid pain and affective disorders, and fewer
pain-free intervals, than do those with episodic migraine. Data on the treatment of chronic migraine are scarce
because most migraine-prevention trials excluded patients who had headaches for ≥15 days per month.
Despite this lack of reliable data, a wealth of expert opinion and a few evidence-based treatment options are
available for managing chronic migraine. Trial data are available for topiramate and botulinum toxin type A,
and expert opinion suggests that conventional preventive therapy for episodic migraine may also be useful.
This Review discusses the evolution of our understanding of chronic migraine, including its epidemiology,
pathophysiology, clinical characteristics and treatment options.
Department of
Neurology and Diener, H.‑C. et al. Nat. Rev. Neurol. 8, 162–171 (2012); published online 14 February 2012; doi:10.1038/nrneurol.2012.13
Headache Center,
University Hospital Introduction
Essen, Hufelandstrasse
55, 45147 Essen,
Chronic migraine is a disabling illness that has a sub­ tension-type headache.18,19 The 2nd Edition of the Inter­
Germany (H.‑C. Diener). stantial effect on the patient’s ability to perform routine national Classification of Headache Disorders (ICHD‑2),
Department of daily activities and on their productivity in the work­ which was published in a revised form (ICHD-2R) by
Neurology, Mayo Clinic
Hospital, 5777 East place.1–3 The burden of chronic migraine, (and its pre­ the IHS in 2006, defines chronic migraine as headaches
Mayo Boulevard, cursor chronic daily headache) has been evaluated on ≥15 days per month for ≥3 months. Headaches on
Phoenix, AZ 85054,
USA (D. W. Dodick).
using both quality of life measures1,4–7 and disability ≥8 days must fulfill the criteria for migraine without
Headache Center, questionnaires.1,5,8,9 These studies indicate that chronic aura, which can be successfully treated with acute-care
University of California migraine has a considerable adverse effect on health- medications such as ergots or triptans (Box 1).20 These
San Francisco, 1701
Divisadero Street, Suite related quality of life and daily functioning, and exacts a criteria have only been in use for the past 6 years and, as
480, San Francisco, CA substantially higher economic toll on both patients and such, this group of patients with severe migraine is still
94115, USA
(P. J. Goadsby). Albert health-care systems than does episodic migraine.10,11 poorly recognized and undertreated by clinicians, as well
Einstein College of Neurologists who identified the needs of patients at as insufficiently studied.
Medicine, Louis and
Dora Rousso Building,
the severe end of the migraine spectrum almost 30 years This Review describes the evolution in nomenclature
1165 Morris Park ago12,13 were only rediscovering conclusions arrived at for chronic migraine and presents the literature on the
Avenue, Room 332, more than a century ago.14 Terms used in the diagnosis of epidemiology, pathophysiology and treatment of this
Bronx, NY 10461, USA
(R. B. Lipton). Danish this group of patients included chronic mixed headache, condition. Since the ICHD-2R20 definition has only been
Headache Center, chronic daily headache15 and transformed migraine.16 available for a short period of time, this Review will also
Department of
Neurology 39, Glostrup
Headache disorders were systematically classified and draw on the literature regarding transformed migraine
Hospital, Nordre defined for the first time in 1988 in the 1st Edition of (Box 2) and/or chronic daily headache, because valida­
Ringvej 57, DK‑2600 the International Classification of Headache Disorders tion studies have identified these disease entities as relat­
Glostrup, Denmark
(J. Olesen). Department (ICHD‑1) by the Headache Classification Committee of ing to almost the same groups of patients as would now
of Neurology, Thomas the International Headache Society (IHS).17 This frame­ be diagnosed as having chronic migraine.21
Jefferson University,
111 South 11th Street,
work enabled the implementation of meaningful and
Suite 8130, reliable epidemiological studies, which demonstrated a Changing nomenclature and definitions
Philadelphia, PA lifetime prevalence of 15–20% for migraine and >50% for The term chronic is used to refer to a condition that
19107, USA
(S. D. Silberstein). has persisted for a long time, but can also imply a
severe condition that is difficult to treat. In migraine
Correspondence to: Competing interests
H.‑C. Diener All authors declare competing interests. See the article online and ­tension-type headache, the use of the term chronic
h.diener@uni-essen.de for full details of the relationships. incorporates all these elements. Before publication of the

162  |  MARCH 2012  |  VOLUME 8  www.nature.com/nrneurol

© 2012 Macmillan Publishers Limited. All rights reserved

IHS classification in 1988, some countries were using
the term chronic mixed headache for patients at the
severe end of the migraine spectrum.22 Neurologists also
recog­nized that some patients who start with episodic
migraine attacks can gradually get increasingly frequent
headaches, which then to some extent lose their migraine
charac­teristics. This presentation was called transformed
migraine; however, the diagnosis could not be applied
universally as only a small subgroup of patients showed
this course.
According to the 1988 IHS classification committee,
the problem caused by earlier nomenclature, in which
these headache subtypes were grouped together under
the term chronic mixed headache,23 could be solved
by providing a separate diagnosis for each recognized
subtype of headache. 17 With the establishment of the
ICHD‑1, a patient at the severe end of the migraine
spectrum could receive a diagnosis of migraine with or
without aura, chronic tension-type headache or head­
ache attributed to medication overuse. However, the
system was criticized because distinguishing between
severe migraine and severe tension-type headache
remained difficult, as both groups of patients tend to
have daily headaches, sometimes with migraine charac­
teristics and sometimes with tension-type headache
characteristics. In addition, patients at the severe end of
the migraine spectrum often exhibit high use or overuse
of acute medications.
An extremely important requirement in the develop­
ment of new drugs is to test candidate agents in patients
with a definite diagnosis. For this reason, until the inclu­
sion of chronic migraine in the ICHD-2R in 2006, all
drug trials for migraine focused on patients with fewer
than six to eight episodes of migraine per month, leaving
the severe end of the migraine spectrum unstudied. In
1997, Silberstein and Lipton published a paper that
redefined the term chronic daily headache.24 Although
this paper made it clear that this term was not actu­
ally a diagnosis, but rather a collective term for severe
chronic headaches (which included the severe end of the
migraine spectrum), the unintended consequence was
that chronic daily headache was used as a diagnosis in
many patients.25
In 2004, ICHD‑2 was published and the diagnostic
category chronic migraine was introduced, for which
unambiguous diagnostic criteria were provided (Box 1).26
However, these criteria turned out to be more restric­
tive than anticipated, which resulted in substantial
confusion. Multiple diagnostic terms and criteria were
used variably in different countries and clinical set­
tings. Realizing that an internationally accepted term
and set of diagnostic criteria were needed for patients
at the severe end of the migraine spectrum, the IHS
classification committee reassembled and a consensus
was reached that the diagnostic term chronic migraine
should replace the problematic terms chronic mixed
headache, transformed migraine and chronic daily head­
ache. New, more-inclusive, but still explicit, diagnostic
criteria for chronic migraine were also agreed on and
included in the appendix of the ICHD-2R, published in
NATURE REVIEWS | NEUROLOGY VOLUME 8  |  MARCH 2012  |  163
© 2012 Macmillan Publishers Limited. All rights reserved
REVIEWS
Key points
■■ Chronic migraine is defined as headache on ≥15 days per month for
≥3 months; headaches on ≥8 days per month must fulfill criteria for migraine
without aura
■■ Treatment requires a multimodal and multidisciplinary approach, including
education, behavioral therapy, regular exercise and preventive drug therapy
■■ Topiramate and botulinum toxin type A have shown modest but significant
efficacy in placebo-controlled trials; other preventive drugs have not been
adequately studied for use in chronic migraine
■■ Chronic migraine can occur with or without medication overuse; patients with
medication overuse should receive advice and support on discontinuation, as
well as multidisciplinary treatment for chronic migraine
■■ The full therapeutic armamentarium for chronic migraine is best offered in
headache referral centers
Box 1 | Current chronic migraine criteria
ICHD‑2 criteria (2004)26
1.5 Complications of migraine
1.5.1 Chronic migraine
Description:
Migraine headache occurring on ≥15 days per month for >3 months in the
absence of medication overuse
Diagnostic criteria:
A. Headache fulfilling criteria C and D for 1.1 Migraine without aura on ≥15 days
per month for >3 months
B. Not attributed to another disorder*
Revised International Headache Society criteria for chronic migraine,
ICHD-2R (2006)20
Appendix 1.5.1 Chronic migraine
A. Headache (tension-type and/or migraine) on ≥15 days per month for
≥3 months*
B. Occurring in a patient who has had at least five attacks fulfilling criteria
for 1.1 Migraine without aura
C. On ≥8 days per month for ≥3 months headache has fulfilled C1 and/or C2
below (that is, has fulfilled criteria for pain and associated symptoms of migraine
without aura):
1. Has at least two of a–d:
(a) Unilateral location
(b) Pulsating quality
(c) Moderate or severe pain intensity
(d) Aggravation by or causing avoidance of routine physical activity (for example,
walking or climbing stairs) and at least one of i or ii:
(i) Nausea and/or vomiting
(ii) Photophobia and phonophobia
2. Treated and relieved by triptan(s) or ergot before the expected development
of C1 above
D. No medication overuse and not attributed to another causative disorder*
*Additional notes relating to these criteria can be found in the original publications.
Abbreviation: ICHD, International Classification of Headache Disorders. ICHD-2 criteria from
Headache Classification Subcommittee of the International Headache Society. The
International Classification of Headache Disorders, 2nd Edition. Cephalagia 24 (Suppl. 1),
24–136 © 2004 by International Headache Society. Reprinted by permission of SAGE.
Reproduced with permission of International Headache Society. ICHD-2R criteria from
Olesen, J. et al. Cephalagia 26(6), 742–746 © 2006 Blackwell Publishing Ltd. Reprinted by
permission of SAGE.
2006 (Box 1).20 Subsequently, the criteria were validated
in Europe and the USA,27–29 and will be incorporated into
the 3rd Edition of the ICHD (ICHD‑3), which is being
prepared. Although the criterion that a patient must have
headaches on ≥15 days per month to fulfill the defini­
tion of chronic migraine is certainly arbitrary, the general
REVIEWS
Box 2 | Previous chronic migraine criteria
Proposed 1995 criteria for transformed migraine31
A. Daily or almost daily (>15 days per month) head pain
for >1 month
B. Average headache duration of >4 h daily (if untreated)
C. At least one of the following:
1. History of episodic migraine meeting any IHS
criteria 1.1 to 1.6*
2. History of increasing headache frequency with
decreasing severity of migrainous features over at
least 3 months
3. Current headache meets IHS criteria for migraine
1.1 to 1.6* other than duration
D. At least one of the following:
1. There is no suggestion of one of the disorders listed
in groups 5–11‡
2. Such a disorder is suggested, but it is ruled out
by appropriate investigations
3. Such a disorder is present, but first migraine attacks
do not occur in close temporal relation to the disorder
*IHS criteria 1.1–1.6 from the ICHD‑1.‡Groups 5–11 from the
ICHD‑1. Abbreviations: ICHD, International Classification of
Headache Disorders; IHS, International Headache Society.
Permission obtained from Wolters Kluwer Health © Silberstein, S. D.
et al. Classification of daily and near-daily headaches: field trial of
revised IHS criteria. Neurology 47(4), 871–875 (1996).
principle that patients with a high number of headache
days have increased disability seems intuitive, and this
group of patients should, therefore, be singled out for
aggressive therapy.
According to the ICHD-2R, the diagnosis of chronic
migraine should not be made in a patient who demon­
strates medication overuse—the most common rever­
sible cause of headaches resembling chronic migraine.
After detoxification, at least half of such patients no
longer show features of chronic migraine, but instead
revert to episodic migraine; the remainder, in whom
medication overuse has been ruled out as the cause, can
be diagnosed with chronic migraine.
Epidemiology
The gradual evolution of the definition of chronic
migraine over time has resulted in varying conclusions
being drawn in studies of its prevalence. Two reviews
that defined chronic headache as being present on
≥15 days per month estimated its global prevalence to
be 3–4%.18,19 A systematic review from 2010 focused
on 12 worldwide, population-based incidence and
prevalence studies that determined rates of chronic
migraine using either the Silberstein–Lipton criteria
for transformed migraine (Box 2),24,30,31 or the current
ICHD-2R criteria for chronic migraine.32 The preva­
lence of chronic migraine in these studies ranged from
0.0% to 5.1% (initial estimates for these rates were typi­
cally in the range of 1.4–2.2%), and varied by WHO-
defined geographical regions as well as sex. 32 These
estimates are imperfect owing to the hetero­geneity of
definitions applied across studies, and the lack of data
from certain regions. Nevertheless, the tar­get popu­lation
is equally well-defined by both the Silberstein–Lipton
transformed migraine criteria and the ICHD-2R term
164  |  MARCH 2012  |  VOLUME 8  www.nature.com/nrneurol
© 2012 Macmillan Publishers Limited. All rights reserved
chronic migraine, so the data presented are likely to give
a reasonably accurate global perspective. The prevalence
of chronic migraine in this systema­tic review also sug­
gests that this condition represents approximately half
of all cases of chronic primary headache. In further
population-based studies—HUNT 2 and HUNT 3, pub­
lished in 2011—the age-adjusted prevalence of chronic
migraine was consistently 0.5% th­roughout an 11-year
follow-up period.33
A cross-sectional study and a cohort analysis were
conducted to identify risk factors that predict onset or
remission of chronic daily headache in a US adult popu­
lation.34 This study revealed an annual incidence rate of
3% for chronic daily headache, and identified several
demographic factors associated with a high prevalence
of this condition, including female sex, white European
heritage, obesity, physician-diagnosed diabetes mellitus
or arthritis, low educational level, and divorce. A high
baseline frequency of headache and acute medication
overuse were also significant risk factors for the progres­
sion from a diagnosis of episodic migraine to a chronic
headache disorder. The critical headache frequency was
defined as ≥10 days per month; patients who experi­
enced headaches at this frequency were at significant
risk of developing chronic daily headache.
Another population-based US study also confirmed
overuse of acute headache medications as an important
risk factor for developing chronic migraine.35,36 Opioid
and barbiturate intakes, in particular, are correlated with
a transition from episodic to chronic migraine owing to
medication overuse.37,38
Although data on the natural history of patients with
chronic migraine is not available (owing to the 10–
15-year timescale that would be required for a popula­
tion-based study of this condition), information from the
American Migraine Prevalence and Prevention study on
the clinical evolution of this condition was published in
2011.39 Longitudinal data over 3 years were analyzed to
determine rates of chronic migraine remission, and
to assess predictors of remission using logistic regres­
sion models. 383 indivi­duals were identified who had
chronic migraine in 2005 and were followed up in 2006
and 2007. Among indivi­duals with chronic migraine at
baseline, 52.7% continued to report this condition for
at least 1 year of follow-up. The study also found that
34% had persistent chronic migraine (defined as chronic
migraine across all 3 years), while only 26% had remis­
sion of chronic migraine (defined as fewer than 10
headache days per month).39 Over 2 years, the indivi­
duals with persistent chronic migraine demonstrated
increased disability, while those with remission showed
decreased disability. Predictors of remission included
a lower baseline headache frequency (15–19 headache
days per month versus 25–31 headache days per month;
OR 0.29, 95% CI 0.11–0.75) and the absence of allodynia
(OR 0.45, 95% CI 0.23–0.89).
Pathophysiology
The pathophysiology of chronic migraine is unclear, but
is likely to be multifactorial and to involve more than

one level of the CNS. The brainstem contains descend­
ing circuitry that can modulate nociceptive processing in
the trigemino­cervical complex.40 Activity-independent
sensitization of central trigeminothalamic pathways is
con­sidered to be a possible cause of the development
of chronic migraine.41 Such sensitization might occur
during repeated migraine attacks through impaired
descending inhibition and/or enhanced descending
facilitation of nociception. 42 Moreover, some experi­
mental data suggest that the ventral posteromedial tha­
lamic nucleus, which receives direct projections from
tri­geminovascular nociceptive neurons,43 can be modu­
lated by standard migraine-preventive drugs, such as
propranolol44 and sodium valproate.45
Several functional imaging studies have demonstrated
abnormal brainstem activation in cases of both episodic
and chronic migraine, 46–49 suggesting that dysfunc­
tion of descending inhibitory pathways might facilitate
migraine attacks. The underlying basis of this dysfunc­
tion is not clear, but repeated episodes of hypoxia during
migraine attacks, leading to abnormal deposition of
nonheme iron and iron-catalyzed free-radical injury,
have been proposed.50 Functional imaging studies have
also demon­strated interictal hypofunction of lateral
descending pain modulatory circuits in patients with
migraine.51 Specifically, these individuals had decreased
activation of the nucleus cuneiformis, which might
account for either descending facilitation of nocicep­
tion or impairment of descending inhibitory pathways
in migraine. The nucleus cuneiformis is responsible for
sensory modulation in animals and humans; it sends
dense neural projections to the rostral ventral medulla,
thereby modulating nociceptive transmission neurons
in the spinal cord and medullary dorsal horn.51,52 The
hyper­excitability of nociceptive circuitry downstream
of the nucleus cuneiformis might contribute to central
sensitization, and is speculated to lead to progressive
changes in the spinal trigeminal nucleus (localized allo­
dynia) and/or the thalamus and spinal cord (generalized
allodynia).51 Enhanced cortical excitability, exceeding
that in patients with episodic migraine or in migraine-
free controls, has also been demonstrated in indivi­duals
with chronic migraine.53,54 Whether this finding is due
to intrinsically increased excitability or to impaired
in­tracortical in­hibitory mechanism­s is unclear.
As previously discussed, overuse of acute pain medica­
tions has a major role in the development of headaches
resembling chronic migraine.28,36,55,56 Experiments in
animal models have revealed persistent pronociceptive
adaptations following exposure to opioids and triptans,
resulting in enhanced sensitivity to stimuli that trigger
migraine in humans.57,58 These findings could provide
insight into the adaptive changes that occur in patients
who have chronic migraine associated with medication
overuse, and thus further elucidate the pathophysiology
of chronic migraine.
Treatment
Until 2007, evidence on the efficacy and safety of pre­
ventive medications used in the treatment of chronic
NATURE REVIEWS | NEUROLOGY VOLUME 8  |  MARCH 2012  |  165
© 2012 Macmillan Publishers Limited. All rights reserved
REVIEWS
migraine had been limited to case studies and open-label
trials. The paucity of randomized controlled trials in this
field can be attributed to the lack of consistent diagnostic
criteria and clinical trial guidelines for chronic migraine,
as well as an unfounded view that this condition is highly
refractory to treatment. Furthermore, there is a notable
dearth of new chemical entities progressing to random­
ized controlled trials for the prevention and/or treatment
of migraine of any sort, which necessarily limits the pool
of studies in chronic migraine. However, some random­
ized controlled trials for medications and devices have
now been conducted in the chronic migraine popula­
tion, and are discussed below. The evidence of efficacy
for therapeutic regimens used to treat chronic migraine
is still of variable quality, and while it is important to
consider the strength of evidence presented, some weight
must also be given to clinical experience with the use of
migraine preventive agents.
Correct diagnosis is essential to devise an appropriate
treatment strategy. Patients who present with chronic
migraine and acute medication overuse need advice and
support to enable them to discontinue the drug. Once
chronic migraine has been diagnosed, manage­ment of
the condition requires an interdisciplinary approach,59
including identification and management of risk factors,
establishment of limits on acute pain medications to mini­
mize the effects of overuse, initiation of nonpharmaco­
logical treatment, and treatment of neuro­psychiatric
disorders (such as depression and anxiety) and other
comorbid conditions (such as obesity) that might con­
tribute to increased attack frequency. These therapeutic
approaches are all based on clinical experi­ence rather
than the results of randomized, placebo-controlled trials.
The primary goals of preventive therapy in patients
with chronic migraine are to reduce the frequency and
severity of attacks, to reduce reliance on acute medica­
tions, and to improve the quality of life. In addition to
education, behavioral therapy and exercise, migraine
prevention by drug treatment has to be considered, as in
patients with episodic migraine.60–65 A treatment strat­
egy that incorporates an effective prophylactic regimen
should be initiated. An effective prophylactic agent
reduces the need for acute medication use, yet only 33%
of patients with chronic migraine are currently using
preventive drugs.35 However, given the degree of noci­
ceptive bombard­ment of the nervous system, causing
peripheral and central sensitization, and the ensuing ten­
dency to overuse acute symptomatic relief medications,
chronic migraine represents a therapeutic challenge for
many clinicians.
Pharmacological treatment
Sodium valproate
The efficacy of sodium valproate in the treatment of chro­
nic daily headache (that is, both chronic migraine and
chronic tension-type headache) was assessed in a study of
70 patients.66 The study showed that sodium valproate was
superior to placebo for a number of outcome parameters,
such as general and maximum pain levels, and pain fre­
quency (Table 1). Larger randomized, placebo-controlled
REVIEWS
Table 1 | Studies of treatment with sodium valproate and topiramate in patients with chronic migraine
Study Study design Population and treatment
Sodium valproate
Yurekli et al. Prospective, double-blind, 70 patients with chronic daily headache
(2008)66* randomized, placebo- (29 with chronic migraine, 41 with chronic
controlled trial tension-type headache)
Treatment (500 mg twice daily) or placebo
for 3 months
Topiramate
Silvestrini Double-blind, randomized, 28 patients with chronic migraine and
et al. (2003)67 placebo-controlled, medication overuse
parallel-group trial 9‑week, low-dose treatment phase (50 mg daily)
Silberstein Double-blind, randomized, 306 patients (intent-to-treat population) with
et al. (2007)69 placebo-controlled, chronic migraine‡ and without medication overuse
parallel-group, multicenter 153 in treatment group and 153 given placebo,
trial 16 weeks’ treatment (100 mg daily; 4‑week
titration period, 12-week maintenance phase)
Diener et al. Double-blind, randomized, 59 patients (intent-to-treat population) with
(2007)68 placebo-controlled, chronic migraine§ most of whom had medication
parallel-group, multicenter overuse (namely, triptans)
trial 32 in treatment group and 27 given placebo,
16 weeks’ treatment (100 mg daily, range
50–200 mg daily)||
*Pain levels were assessed using a visual analog scale. ‡Defined as ≥15 headache days per 28-day period, of which at least 50% were migraine headaches. §Defined as ≥15 monthly migraine
days for ≥3 months before trial entry, regardless of acute medication overuse. ||Patients included if they had ≥12 migraine days during the 28-day baseline phase.
trials are required for further evaluation of chronic
migraine treatment with sodium valproate.
Topiramate
The encouraging results from a small placebo-controlled
trial67 of topiramate in patients with chronic migraine
prompted further investigation into the efficacy of this
drug in large, rigorously controlled studies (Table 1).
Two separate studies in Europe and the USA showed that
topira­mate at a dose of 100 mg daily was effective as a
preventive therapy for chronic migraine.68,69 The key dif­
ference between the two studies was that patients were
allowed to take acute rescue medication as usual in the
European trial,68 but not in the US trial.69 Remarkably,
the benefits of topiramate extended to the subgroup
of patients who were overusing acute medications, as
demon­strated by the significant reductions in mean
monthly migraine days in this group compared with
the placebo group (Table 1).68 Topiramate use was also
associated with a decreased number of days per month
that patients were taking acute medication (reductions of
3 days per month in the topiramate group versus 0.7 days
per month in the placebo group); however, this difference
was not statistically significant.68 An interesting finding
in the European study was the lack of a placebo response,
perhaps attributable to the fact that patients continued
to overuse acute headache medications throughout
the study.68
Adverse effects observed in the European study were
mild to moderate in severity, and consistent with those
noted in previous clinical trials of topiramate: pares­
thesia (53% in the treatment group versus 7% in the
placebo group) and nausea (9% in the treatment group
versus 0% in the placebo group) were both reported.68 In
the US study, commonly reported adverse effects in the
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© 2012 Macmillan Publishers Limited. All rights reserved
Results
All chronic daily headache patients: decreased
maximum pain levels and pain frequency, no change
in general pain levels
Chronic migraine subgroup: significant improvement
in general and maximum pain levels, and pain frequency
Baseline headache frequency: 20.8 days per month
Mean 28-day headache frequency: topiramate 8.1 ± 8.1
vs placebo 20.6 ± 3.4 (P <0.0007)
Significant reduction in mean number of migraine days
per month (P = 0.01): topiramate 6.4 ± 5.8 days
(baseline frequency 17.1 days) vs placebo 4.7 ± 6.1 days
(baseline frequency 17.0 days)
Significant reduction from baseline in the mean number
of migraine days per month (P = 0.02): topiramate
3.5 ± 6.3 days (baseline frequency 15.5 ± 4.6) vs placebo
0.2 ± 4.7 days (baseline frequency 16.4 ± 4.4)
topiramate group included paresthesia, upper respiratory
tract infection and fatigue.69 No serious adverse effects
were reported in the treatment or placebo groups of either
study.68,69 Both trials demonstrated that topiramate was
effective and safe in populations of patients with chronic
migraine, and efficacy seemed to be maintained regardless
of the presence or absence of acute medication overuse.70
Botulinum toxin type A
Botulinum toxin type A has been reported to relieve
the pain associated with a variety of conditions,71–74 and
this agent is currently approved for use as a prophy­lactic
therapy in patients with chronic migraine in more than 40
countries, including the UK and the USA. Unlike its well-
known ability to block signaling at the neuro­muscular
junction, the mechanism of action of botuli­num toxin
type A in migraine relief is not at all understood. This
drug is thought to inhibit sensitization of peripheral tri­
geminal sensory fibers, which in turn modulates the activ­
ity of central trigeminal neurons and thus indirectly leads
to inhibition of migraine headache.75,76 None of the work
done to support this contention has been conducted in
patients with migraine, but instead has been carried out
in established experimental models of trigeminovascular
and peripheral nociception.77
A number of placebo-controlled trials in patients with
episodic migraine or chronic daily headache failed to
show efficacy of botulinum toxin type A.78–83 Post hoc
analyses, however, indicated that patients with frequent
migraine headaches might benefit from this treatment.84
Accordingly, the Phase III Research Evaluating Migraine
Prophylaxis Therapy (PREEMPT 1 and 2) multicenter
randomized clinical trials were conducted to evaluate the
efficacy and safety of botulinum toxin type A as a prophy­
lactic treatment for adults with chronic migraine. A total

Table 2 | Results from phase III trials of botulinum toxin type A*
Study details End points
PREEMPT 185 Primary: change in frequency of headache
(56 sites in the episodes at week 24 compared with baseline
USA) Secondary: change in frequency of headache
days at week 24 compared with baseline
PREEMPT 286 Primary: change in frequency of headache
(50 sites in the USA days at week 24 compared with baseline
and 16 sites in Secondary: change in frequency of headache
Europe) episodes at week 24 compared with baseline
Pooled analysis of Not applicable
results from
PREEMPT 1 and 287
*Similar study designs were used in both trials: 24-week, double-blind, parallel-group, placebo-controlled phase followed by a 32-week open-label phase. Abbreviation: PREEMPT, Phase III
Research Evaluating Migraine Prophylaxis Therapy.
of 1,384 patients with chronic migraine were enrolled
across both trials (Table 2).85–87 Patients were strati­fied
into groups according to whether they were overusing
acute headache medications at baseline, and were ran­
domly assigned in a 1:1 ratio to either botulinum toxin
type A or placebo injections. A total dose of botulinum
toxin type A of 155 U was administered to 31 sites in
seven head and neck muscles.85–87 The studies incor­
porated a double-blind phase and an open-label phase,
although the efficacy of blinding was not evaluated.
The PREEMPT study results demonstrated significant
improvements at the population level in multiple mea­
sures of headache symptoms, as well as improvements
in patients’ functioning, vitality, psychological distress,
and overall health-related quality of life, in response to
treatment with botulinum toxin type A.
Botulinum toxin type A versus topiramate
Although the indirect comparison of drugs across trials
has many limitations, comparing the effect size of differ­
ent therapies is of importance to both the clinician and
the patient. We have compared the findings from the
largest available randomized, placebo-controlled trial
evaluating the efficacy and safety of topiramate in the
treatment of chronic migraine69 with the pooled results
from the two PREEMPT studies evaluating botulinum
toxin type A.87 These studies were not directly compa­
rable, and the end points differed between the studies;
hence, some adjustment is necessary to compare their
results. The primary end point in the topiramate study—
the change from baseline in the mean monthly number
of migraine and/or migrainous headache days (evalu­
ated at week 16)—is similar to a secondary end point
used in an analysis of the pooled PREEMPT data—the
change from baseline in frequency of migraine or prob­
able migraine days (evalu­ated at week 24). These end
points can, therefore, be used for the purpose of com­
paring the two treatments: a reduction of 8.8 migraine or
NATURE REVIEWS | NEUROLOGY VOLUME 8  |  MARCH 2012  |  167
© 2012 Macmillan Publishers Limited. All rights reserved
REVIEWS
Results
No significant improvement in frequency of headache episodes
Significant reduction in frequency of headache days (P = 0.006)
Significant reduction in frequency of headache days (P <0.001)
Significant improvement in frequency of headache episodes (P = 0.003)
Significant reduction in headache days after 6 months in treatment groups vs
placebo groups (P <0.001), therapeutic gain of 11%: treatment, 8.4 days (baseline
frequency 19.9 days) vs placebo 6.6 days (baseline frequency 19.8 days)
Significant improvements in treated patients vs placebo groups in other efficacy
variables: frequency of migraine episodes (P = 0.004), migraine days (P <0.001),
severe headache days (P <0.001); cumulative hours of headache per day (P <0.001);
proportion of patients with severe disability (P <0.001)
Intake of medications to treat acute migraine attacks was not different between
placebo and treatment groups (however, in post hoc analysis, intake of triptans was
significantly reduced in the treatment group)
probable migraine days with botulinum toxin type A is
compared with a reduction of 6.4 migraine or migrain­
ous headache days after treatment with topiramate.
Both botulinum toxin type A and topiramate studies
demonstrated a significant between-group difference
in the number of headache days, favoring treatment
over placebo. The mean between-group differences
(treatment minus placebo) in change from baseline of
the number of headache days are comparable for botu­
linum toxin A and topiramate (2.3, P <0.001 versus 1.8,
P = 0.010, respectively) suggesting similar efficacy of
both drugs.
For topiramate, the number of patients needed to treat
(NNT) to achieve a significant reduction in the rate of
migraine or probable migraine days was 12.5 versus an
NNT of 8.0 for botulinum toxin type A. However, the
topiramate dataset was much smaller than the pooled
PREEMPT data, which might influence the results as the
NNT is more reliable with large datasets.
Fewer treatment-related adverse effects occurred
with botulinum toxin type A in the PREEMPT studies
(29.4% treatment group versus 12.7% placebo) than in
the topiramate study (65.0% treatment group versus
42.9% placebo). Likewise, fewer patients discontinued
treatment owing to adverse effects in the PREEMPT
studies (3.8% treatment group versus 1.2% placebo) than
in the topiramate trial (10.9% treatment group versus
6.1% placebo). Topiramate is arguably a poor choice
of comparison therapy owing to its frequent systemic
adverse effects; however, other preventive treatments,
such as β‑blockers and tricyclic antidepressants, have
not been sufficiently studied for use in patients with
chronic migraine, and randomized controlled trials of
these agents would be of value.
Most patients are referred to tertiary headache centers
because they cannot achieve migraine prevention with
β‑blockers, flunarizine or amitriptyline. Preventative
therapy with topiramate or botulinum toxin type A
REVIEWS
should be offered to these patients. Owing to cost con­
siderations, prevention should be initiated with topira­
mate, and botulinum toxin type A should be offered to
patients in whom topiramate is ineffective, not toler­
ated, or contraindicated. Interestingly, studies involv­
ing patients with chronic migraine who have coexisting
acute medication overuse suggest that these patients
also benefit from either topiramate68 or botulinum toxin
type A (approximately 65% of patients in the PREEMPT
studies overused acute medication).85–87 At present, we
are not aware of any randomized trials that have investi­
gated whether topiramate or botulinum toxin type A is
as effective as detoxification in patients with medication
overuse, or whether some subgroups of individuals with
chronic migraine might do better with one or other of
these strategies.
Treatment with limited supporting evidence
Levetiracetam was studied in a multicenter, random­
ized, placebo-controlled, crossover study that included
patients with either chronic migraine or chronic
­tension-type headache.88 The primary end point was the
highly desirable—but somewhat stringent—outcome
of freedom from headache. Of 96 patients recruited
to the study, 73 had chronic migraine. The study failed to
meet its primary efficacy end point, although levetirace­
tam was associated with a nonsignificant 3.9% increase
in the headache-free rate versus placebo. Nevertheless,
some secondary end points were achieved, including a
reduction in the number of headache days per month
(P = 0.0325), reduced disability (P = 0.0487), and reduced
pain severity (P = 0.0162).88 The use of levetiracetam in
patients with chronic migraine cannot currently be
recom­mended on the basis of these data.
Nonpharmacological treatment
Occipital nerve stimulation
Two studies have evaluated the safety and efficacy of
occipital nerve stimulation for the treatment of chronic
migraine. In a multicenter, prospective, randomized,
single-blind, sham-treatment-controlled feasibility study,
published in 2011, 66 patients who met the ICHD‑2 cri­
teria for chronic migraine received an occipital nerve
block, and those with a positive response to this test (a
≥50% reduction in migraine pain within 24 h of the injec­
tion of bupivacaine into each greater occipital nerve dis­
tribution) underwent simulator implantation and were
randomly allocated to one of three treatment groups:
adjustable stimulation (28 patients), preset stimulation
(16 patients), or medical management (17 patients).89
An ancillary group of five patients who did not respond
to the nerve block test also underwent implantation
and were managed with adjustable stimulation. Res­
ponder rates at 3 months (defined as a ≥50% reduction
in migraine days per month, or a ≥3-point reduction in
average pain intensity from baseline) for these treat­ment
groups were 39% (adjustable stimulation), 6% (preset
stimulation), 0% (medical management) and 40% (ancil­
lary group on adjustable stimu­lation). Lead mi­gration
occurred in 12 of 51 patients (24%).
168  |  MARCH 2012  |  VOLUME 8  www.nature.com/nrneurol
© 2012 Macmillan Publishers Limited. All rights reserved
In the second study, which also defined chronic
migraine according to the ICHD‑2 criteria, 125 patients
from 13 US centers participated in a prospective, ran­
domized, blinded, 12-week feasibility study using a
different stimulation system.90 These patients were ran­
domly allocated in a 1:1 ratio to either sham stimulation
(10 μs pulses, 2 Hz, <1 mA; 1 s on-simulation and 90 min
off-stimulation cycle) or active intermittent occipital
nerve stimulation (250 μs pulses, 60 Hz, 0.0–12.7 mA)
The primary end point was the decrease from base­
line in the number of migraine days per month, which
was evalu­ated 12 weeks after device implantation. This
parameter did not differ significantly between the
active-treatment and sham-treatment groups, which
demonstrated reductions of 5.5 and 3.9 migraine days
per month, respectively. Interestingly, when the two
groups were stratified for medication overuse, the dif­
ference between treatment arms increased only in
patients without overuse (but was still not statistically
significant); reductions of 5.9 and 2.6 migraine days
per month in the active-treatment and sham-treatment
groups, respectively. The most frequent device-related
adverse effects and complications included non-target-
area sensory symptoms (18%), implant-site pain (17.3%),
infection (15.1%), residual incision-site pain (7.9%), and
lead migration (6.8%).
On the basis of the results from these two studies,
occipital nerve stimulation could potentially be an effec­
tive treatment for patients with drug-refractory chronic
migraine and, in fact, this treatment has already been
approved in the USA. Two randomized, sham-controlled
phase III studies were planned to begin in 2011.
Acupuncture and behavioral sleep modification
Our literature search yielded only three randomized
controlled trials that investigated nonpharmaco­logical
treatment in patients with chronic daily headache or
trans­formed migraine. All other such studies recruited
patients with episodic migraine.91 In a study of 74 patients
with chronic daily headache who were randomly allo­
cated to either medical management alone or medical
management and acupuncture, only the combination
therapy was associated with improved clinical outcome.92
A pilot trial investigated the efficacy of safflower (Car­
thamus tinctorius) seed extract.93 Injections of either
normal saline or safflower seed extract were adminis­
tered into a series of acupuncture points in 40 patients
with chronic daily headache. Compared with normal
saline injections, safflower seed extract injections
resulted in a significantly higher reduction in scores
on the Headache Impact Test‑6, which is used to assess
headache-related quality of life.
In another study, 43 women with transformed
migraine were randomly assigned to either behavioral
sleep modification—consisting of scheduled bedtimes
that allowed 8 h of time in bed; elimination of tele­
vision, reading and listening to music while in bed;
visuali­za­tion techniques to shorten the time to sleep
onset; moving consumption of food and liquids to >4 h
and >2 h before bedtime, respectively; and eliminating
 REVIEWS

naps—or placebo.94 The intervention was associated with
a significant reduction in headache frequency. Owing
to their small sample sizes, these studies are, at best,
hypothesis-generating.
Conclusions
Chronic migraine is a disabling, poorly recognized and
undertreated disorder. Only 20% of patients who fulfill
the IHS criteria for chronic migraine are diagnosed with
the condition,10,35 highlighting the need for improved
recognition. Full support and universal use of the
ICHD-2R diagnostic criteria will help to identify patients
with chronic migraine who would benefit from preven­
tive treatment. With the very few existing randomized
controlled trials of treatments for chronic migraine, a
great need remains for further studies of existing drugs
to be conducted, as well as for the development of new
chemical agents and nonpharmacological therapies.
Review criteria
A MEDLINE search was conducted for articles published
in 2008–2011 using the search terms “chronic migraine”,
“transformed migraine”, “chronic daily headache”
and “medication overuse headache”. The personal
literature collection of the authors was also searched for
relevant publications. In addition, the authors reviewed
the results of a MEDLINE search conducted by Imprint
Publication Science for Allergan, which had been included
in a document submitted to the FDA before approval of
botulinum toxin type A in patients with chronic migraine.
Allergan also provided copies of articles listed therein that
could not be accessed by the authors’ university library.

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Acknowledgments
The authors thank A. O. Horner and P. Kukovich of
Imprint Publication Science, for their assistance with
the literature search and language editing. They also
performed the systematic literature search for Allergan
described in the Review criteria. H.‑C. Diener
acknowledges the support of the German Research
Foundation (Deutsche Forschungsgemeinschaft), the
Federal Ministry of Education and Research
(Bundesministerium für Bildung und Forschung) and
the European Union. D. W. Dodick acknowledges grant
support from the National Institute of Neurological
NATURE REVIEWS | NEUROLOGY VOLUME 8  |  MARCH 2012  |  171
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Disorders and Stroke (NINDS) and the NIH.
P. J. Goadsby has consulted for, advised or collaborated
with NINDS, the Netherlands Organization for Scientific
Research, the Organization for Understanding Cluster
Headaches, and the Organization for the
Understanding of Cluster Headache (UK). R. B. Lipton
has acted as a reviewer for the National Institute on
Aging and NINDS. Professor Lipton acknowledges grant
support from the Migraine Research Foundation, the
National Headache Foundation, and the NIH (grants
PO1AG03949, PO1AG027734, RO1AG025119,
RO1AG022374‑06A2, RO1AG034119, RO1AG12101,
© 2012 Macmillan Publishers Limited. All rights reserved
REVIEWS
K23AG030857, K23NS05140901A1 and
K23NS47256). S. D. Silberstein is on the advisory
panel for and receives honoraria from NINDS.
Author contributions
H.‑C. Diener, D. W. Dodick and S. D. Silberstein
contributed to all aspects of this Review. P. J. Goadsby
and J. Olesen contributed to the discussion of content,
writing and review and/or editing of the manuscript
before submission. R. B. Lipton contributed to the
discussion of content and review and/or editing of the
manuscript before submission.